Skipper Lisa, Li Yi, Bonnard Carine, Pavanni Ratnagopal, Yih Yuen, Chua Eva, Sung Wing-Kin, Tan Louis, Wong Meng-Cheong, Tan Eng-King, Liu Jianjun
Population Genetics, Genome Institute of Singapore, Singapore.
Hum Mol Genet. 2005 Dec 1;14(23):3549-56. doi: 10.1093/hmg/ddi376. Epub 2005 Nov 3.
Parkinson's disease (PD) is a complex neurodegenerative disorder whose aetiologies are largely unknown. To date, mutations in six genes have been found causal for some rare familial forms of the disease and common variation within at least three of these is associated with the more common sporadic forms of PD. LRRK2 is the most recently identified familial PD gene, although its role in sporadic disease is unknown. In this study, we have performed the first comprehensive evaluation of common genetic variation within LRRK2 and investigated its contribution to risk of sporadic PD. We first characterized the linkage disequilibrium within LRRK2 using a panel of densely spaced SNPs across the gene. We then identified a subset of tagging-SNPs (tSNP) that capture the majority of common variation within LRRK2. Both single tSNP and tSNP haplotype analyses, using a large epidemiologically matched sporadic case-control series comprising 932 individuals, yielded significant evidence for disease association. We identified a haplotype that dramatically increases disease risk when present in two copies (OR=5.5, 95%CI=2.1-14.0, P=0.0001). Thus, we provide the first evidence that common genetic variation within LRRK2 contributes to the risk of sporadic PD in the Chinese population.
帕金森病（PD）是一种复杂的神经退行性疾病，其病因大多未知。迄今为止，已发现六个基因的突变导致了该疾病的一些罕见家族形式，并且其中至少三个基因内的常见变异与更常见的散发性PD形式相关。LRRK2是最近鉴定出的家族性PD基因，但其在散发性疾病中的作用尚不清楚。在本研究中，我们首次对LRRK2内的常见基因变异进行了全面评估，并调查了其对散发性PD风险的贡献。我们首先使用一组跨越该基因的密集间隔单核苷酸多态性（SNP）来表征LRRK2内的连锁不平衡。然后我们鉴定了一组标签SNP（tSNP），其捕获了LRRK2内的大部分常见变异。使用包含932名个体的大型流行病学匹配的散发性病例对照系列进行的单tSNP和tSNP单倍型分析均产生了疾病关联的显著证据。我们鉴定出一种单倍型，当以两个拷贝存在时会显著增加疾病风险（比值比=5.5，95%置信区间=2.1-14.0，P=0.0001）。因此，我们提供了首个证据，证明LRRK2内的常见基因变异会增加中国人群散发性PD的风险。
